effect of pegvisomant on gh/igf-i relationship in ghd

Conditions: Severe Adult Growth Hormone Deficiency

Summary: approximately 50% of middle-aged patients with severe aghd have a normal age-related serum igf-i. it remains unclear if in these individuals serum igf-i is gh dependent or independent. this study compared the relationship between gh and serum igf-i in two cohorts of male patients with severe aghd; one with normal and the other with subnormal age-related serum igf-i values. the gh receptor antagonist - pegvisomant was be used to specifically inhibit gh action and the changes in markers of the gh axis, such as serum igf-i, igfbp-3, gh and ghbp were measured.

there is an increasing reliance on serum insulin-like factor-i (igf-i) in the management of disturbances of the growth hormone (gh) axis. igf-i is predominantly, but not exclusively, regulated by gh secreted from the pituitary, with the majority of circulating igf-i being hepatic in origin. in parallel with the age-related decline in gh secretion, circulating levels of igf-i fall with age (1). for a given gh level women have lower serum igf-i levels than men, indicative of a relative gh resistance (1,2). nutrition-related factors are known to affect gh, igf-i and their relationship. obesity is associated with low gh production, but increased gh sensitivity resulting in relatively high igf-i for given gh (3-6). deprivation of important nutrients during fasting is known to stimulate gh, whilst reducing igf-i (7-9). in vitro studies demonstrated complex role of insulin in igf-i generation. insulin stimulates hepatic igf-i production directly by increasing igf-i mrna synthesis and indirectly by enhancing the effect of gh (10,11). by decreasing insulin-like growth factor 1 and 2 (igfbp1-2), insulin may also affect bioavailability of igf-i (12-13). in acromegaly, igf-i is an important marker for diagnosis and monitoring of disease activity. if patients are treated with a gh receptor antagonist, igf-i becomes the only useful biochemical marker for monitoring disease activity. gh deficiency in adults is associated with increased morbidity (14-16). in patients with pituitary disease there has been great progress in the recognition and treatment of this disorder. there is increasing awareness of gh deficiency, not only as a complication of the long-recognised causes of hypopituitarism, but also in the setting of traumatic brain injury and subarachnoid haemorrhage (17). the phenotype of severe adult ghd has been described but many of the features lack specificity and biochemical confirmation of the diagnosis is necessary. the port stevens consensus on severe adult ghd relies on the measurement of stimulated gh secretion for confirmation of the diagnosis with a peak gh of \<3 µg/l, in one or two stimulation tests, depending on the number of other pituitary hormone deficiencies (18) gh replacement therapy relies on measurement of serum igf-i for dose titration, with the biochemical goal being of placing circulating igf-i within age- and gender-related reference range, preferably between 0 and +1 sds (19). the port stephens consensus recognises the apparent paradox that approximately 50% of middle-aged patients diagnosed with severe ghd by a peak stimulated gh levels of \<3 µg/l have a pre-treatment igf-i within the reference range. in untreated severe ghd of adult onset and predominately in men, serum igf-i may even be in the upper half of reference range. in other words, before treatment these patients already have an igf-i that would be regarded as satisfactory response to gh replacement therapy. prima facia, it is difficult to reconcile a serum igf-i within the reference range and a diagnosis of ghd. inevitably, it poses the question if factors other than gh are regulating circulating igf-i levels in such patients. pegvisomant is a gh analogue that binds to, but does not activate the gh receptor and has been shown to normalise igf-i in up to 97% of patients with acromegaly (20). we used pegvisomant to study the relationship between gh and igf-i in patients with severe adult ghd and investigate whether igf-i in such patients, is particularly gh-dependent.

Eligibility criteria:
inclusion criteria: * over 18 years of age * confirmed severe aghd * gh response \<9 mu/l (preferably \<4) to insulin-induced hypoglycaemia or glucagon stimulation test plus (these tests will have taken place as part of routine management). * full, stable pituitary replacement therapy * willing to provide informed consent exclusion criteria: * unwilling to provide written consent * current gh therapy * pharmacological doses of glucocorticoids * any acute illness

Keywords: growth hormone insulin-like growth factor 1 pegvisomant